This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Biliary atresia is the most common cause of cholestasis in infants and the most frequent indication for pediatric liver transplantation. The disease results from a destructive inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tract. Although little is known about the etiology or pathogenesis of biliary atresia, epidemiologic and virologic studies point to a complex trait disorder, in which environmental factors trigger an inflammatory process that recognizes and abnormally targets the biliary system during a specific phase of postnatal development. Based on these data, the following unifying pathogenesis model can be preliminarily proposed: Regardless of initiating (environmental) and modifying (genetic) factors for disease development, the inflammatory and fibrosing destruction of the biliary epithelium is common to all clinical forms of biliary atresia. In this setting, the potential decrease of this inflammatory component by corticosteroid treatment may result in improved bile flow and better outcome after portoenterostomy. Therefore, in this clinical trial we propose to objectively determine whether corticosteroid treatment improves bile flow in infants with biliary atresia. The significance of the proposed trial is that it will determine whether corticosteroids are an effective medical treatment to improve bile drainage and long-term outcome, and whether its use reduces the need for liver transplantation in infants with biliary atresia. The trial will be performed by the NIH-supported Biliary Atresia Research Consortium (BARC). BARC has the infrastructure to prospectively follow a sufficiently large number of patients and to collect samples necessary for clinical research studies addressing etiology, pathogenesis, diagnosis, and treatment of children with biliary atresia. HYPOTHESES Our overall hypothesis is that therapy with corticosteroids following portoenterostomy will improve bile drainage and long-term outcome in infants with biliary atresia. This hypothesis will be tested through the following hypotheses: 1a: The probability of an infant having good bile drainage at 6 months after portoenterostomy (as defined by a serum total bilirubin level &lt;1.5 ml/dL) will be greater in infants who are treated with corticosteroids than those treated with placebo. 1b: Improved bile drainage (as defined by a serum total bilirubin level &lt;1.5 mg/dL);will remain for a longer period in infants treated with corticosteroids than those treated with placebo. 2: Survival without transplantation will be greater at 24 months of age in infants treated with corticosteroids than those treated with placebo. 3: Weight and height Z-scores at 12 and 24 months of age will be greater in the infants treated with corticosteroids than those treated with placebo. 4a: Treatment with corticosteroids leads to improved bile drainage (hypothesis 1) which, in turn, increases the probability that an infant will achieve vitamin sufficiency of each of the fat-soluble vitamins following supplementation of ADEK[unreadable]. 4b: Treatment with corticosteroids leads to improved bile drainage(hypothesis 1) which, in turn, reduces the dose required for supplementation and the length of time of supplementation for each of the fat-soluble vitamins. 5: The incidence of ascites will be decreased at 12 and 24 months of age in infants treated with corticosteroids than those treated with placebo. SPECIFIC AIMS: Portoenterostomy is the only operative procedure used currently to improve bile drainage in infants with biliary atresia. Although prompt diagnosis and surgical intervention may induce bile flow, progression to end-stage liver disease occurs in over 50% of the patients by 2 years of age. The biological basis for the progression of liver disease after portoenterostomy is not fully understood, but the presence of hepatobiliary inflammation and proinflammatory cytokines at the time of diagnosis suggests that inflammatory forces mediate, at least in part, the progressive injury. Consistent with this concept, prior clinical reports of corticosteroids as an adjuvant treatment following portoenterostomy for biliary atresia suggest that high doses of corticosteroids may lead to prolonged jaundice-free survival without liver transplantation. Based on these reports, we propose a multi-center randomized, double-blinded, placebo-controlled trial to prospectively determine the efficacy of corticosteroids on the outcome of infants with biliary atresia. The trial will be conducted by the NIDDK-funded network of ten clinical centers comprising the Biliary Atresia Clinical Research Consortium (BARC) whose goal is to study the etiology, pathogenesis, diagnosis, and treatment of infants with biliary atresia. The specific aims in support of this goal are below: Aim 1: To determine whether corticosteroid therapy decreases serum bilirubin concentration after portoenterostomy. Aim 2: To determine whether corticosteroid treatment after portoenterostomy will improve outcome as defined by survival without transplantation at 24 months of age. Aim 3: To determine whether corticosteroid treatment after portoenterostomy will improve growth of infants with biliary atresia. Aim 4: To determine whether corticosteroid treatment improves biochemical indicators of each of the fat-soluble vitamins after supplementation with standard doses. Aim 5: To determine whether corticosteroid treatment after portoenterostomy will decrease the incidence of persistent ascites or ascites that requires medical treatment. BACKGROUND AND SIGNIFICANCE Biliary atresia is a progressive fibro-inflammatory cholangiopathy of infancy that results in complete obliteration of the entire or portions of the extrahepatic biliary tree within 12 weeks of birth. This obstruction results in impaired bile drainage, reactive proliferation of intrahepatic bile ducts, cholestasis, and ongoing hepatocellular injury. If no therapy is implemented, ongoing injury leads to biliary cirrhosis, portal hypertension, and end-stage liver disease, leaving liver transplantation as the only therapeutic option for long-term survival. Biliary atresia is the most common cause of prolonged conjugated hyperbilirubinemia in neonates and is the most frequent indication for liver transplantation in children, accounting for 40-50% of all pediatric liver transplants. The disease respects no geographic boundaries;it occurs worldwide and affects approximately 1 in 8,000 to 1 in 15,000 live births. The health care costs associated with medical/surgical intervention and transplantation for infants with biliary atresia are significant, estimated to reach $65 million/year in the United States. From a total of $77 million spent annually on pediatric liver transplantation in the United States, about half relates to biliary atresia. Notably, this sum of money covers 0.2% of total health care expenditures for children, even though these children represent only 0.0006% of the total pediatric population. This disproportionate expenditure could be decreased by half if improved medical therapies were developed that reduce the need for liver transplantation. There are two well-recognized clinical forms of biliary atresia: embryonic and perinatal. These forms share the cardinal features of jaundice, acholic stools, and hepatomegaly but differ in the presence of associated anomalies, the timing of onset of jaundice, and perhaps clinical outcome. The embryonic form of biliary atresia (also referred to as &quot;congenital&quot;or "fetal") accounts for 10 to 20% of cases and is defined by the presence of congenital nonhepatic anomalies and earlier onset of disease. Among congenital nonhepatic anomalies, patients may have defects in laterality (or asymmetric left-right determination of visceral organs) poly- or asplenia, and gastrointestinal or cardiovascular anomalies. Infants present with pathologic jaundice at birth or shortly thereafter, frequently overlapping with physiologic jaundice such that there is no jaundice-free interval. There is some evidence that patients with this clinical form have worse outcome following portoenterostomy. The perinatal forms of biliary atresia (also referred to as acquired "or postnatal") accounts for the majority of the cases (80-90%) and occurs in the absence of other congenital anomalies. Most of the infants are born at term with an appropriate weight for gestational age. They have a variable jaundice-free interval after birth but develop jaundice, acholic stools, and dark-colored urine within the first few weeks of life. In contrast to the clinical setting observed in infants with the embryonic form, the presence of a jaundice-free period is more consistent with a biliary injury that results from a perinatal or early postnatal insult. Efforts to determine the biologic relationship of potential pathogenic mechanisms are particularly important to understand the molecular basis of the clinical forms and to develop new diagnostic/therapeutic modalities for infants with biliary atresia. Theoretical considerations of the pathogenesis of biliary atresia are based largely on epidemiologic and clinical features, reported predisposing genetic factors, and pace of disease progression. Based on these observations, five mechanisms have been proposed to play important roles in the pathogenesis of biliary atresia: defect in morphogenesis of the biliary tract, defect in fetal/prenatal circulation, immunologic dysregulation, viral infection, and environmental toxin exposure. Corticosteroid treatment may improve bile drainage following portoenterostomy by at least two proposed mechanisms. In the first, at pharmacologic doses, corticosteroids may stimulate bile salt-independent bile flow by inducing expression of hepatic Na-K adenosine triphosphatase, a sinusoidal transporter that helps maintain the osmotic and electrical forces necessary for bile formation. In the second, corticosteroids have well-described anti- inflammatory and immunomodulatory properties. For example, administration of corticosteroids decreases the number and immune response of lymphocytes, with suppression of interleukin (IL)1, IL2, IL3, IL6, TNF, and interferon gamma. The anti-inflammatory properties of corticosteroids also result from a much broader effect in a variety of cells, such as the decrease in production of cytokines, adhesion molecules, and metabolic signals by macrophages, monocytes, basophils, fibroblasts, and endothelial cells. These anti-inflammatory functions modulate both humoral and cellular immunity, and have assured a central role for corticosteroids in the treatment of allergic and immunologic disorders. With the increasing body of evidence that the livers of infants with biliary atresia produce inflammatory mediators, treatment of corticosteroids has the potential to decrease inflammation, edema, and progression of fibrosis. The effectiveness of corticosteroid therapy to improve bile drainage and clinical outcome in infants with biliary atresia has not been evaluated prospectively to date. However, four retrospective reports suggest that corticosteroids may improve bile drainage and outcome of patients with biliary atresia. In an initial clinical report, a short course of high doses of methylprednisolone in infants/children with reduced bile flow at variable lengths of time from the initial portoenterostomy for biliary atresia increased daily bilirubin excretion and decreased serum levels of bilirubin, alkaline phosphatase, and aminotransferases. Serum levels of bilirubin and aminotransferases also improved in another group of infants with biliary atresia receiving prednisolone 6-8 days after portoenterostomy, but the duration of corticosteroid use was not clearly stated. More recently, two reports described high doses of corticosteroids soon after portoenterostomy followed by a taper over 6-12 weeks in infants with biliary atresia. Both reports suggested improved bile drainage and increased survival with native liver in over 70% of patients.